The American Diabetes Association has declared type 2 diabetes (T2D) a public health crisis. T2D begins as a state of compensated insulin resistance; frank disease develops when ~50% of insulin-producing pancreatic islet ?-cells of affected individuals undergo cell death. Endoplasmic reticulum (ER) stress has emerged as a central underlying mechanism that drives the progression from obesity to T2D. In the periphery, obesity-induced ER stress can impair proper insulin signaling. In pancreatic islets, glucotoxicity and lipotoxicity-induced ER stress contributes to ?-cell dysfunction and apoptosis. We have identified IRE1? as the master unfolded protein response regulator that determines cell fate under ER stress, and have demonstrated that IRE1? inhibitors we call KIRAs (Kinase Inhibitor RNase Attenuators) block ER stress-driven ?-cell dysfunction and apoptosis in vivo. We believe that KIRAs will also act to reduce peripheral insulin resistance and propose proof-of-concept experiments addressing insulin signaling in the liver. We will demonstrate that KIRAs can correct faulty insulin signaling in ER stress-challenged liver cells and optimize their profile to support subsequent development in T2D. We believe a drug intervention that addresses both peripheral insulin resistance and pancreatic ?-cell dysfunction and apoptosis has great disease-modifying potential. The specific aims of the proposal are: 1: Demonstrate that KIRAs can correct insulin signaling in a cellular model of insulin resistance; and, 2: Optimize KIRAs to impart a profile that supports development in T2D.